Mood disorders are among the most prevalent forms of mental illness. Severe forms of mental illness affect 2%-5% of the US population and up to 20% of the population suffers from milder forms of the illness. The economic costs to society and personal costs to individuals and families are enormous.
Depressive syndromes occur in the context of a vast number of mental and medical illnesses. Depression is a central feature of major depressive disorder and bipolar disorder. Anxiety disorders, such as post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, panic disorder, social phobia, and generalized anxiety disorder, are often accompanied by depression. Alcohol and other substance abuse or dependence may also co-exist with depression. Research shows that mood disorders and substance abuse commonly occur together. Depression also may occur with other serious medical illnesses such as heart disease, stroke, cancer, HIV/AIDS, diabetes, and Parkinson's disease. People who have depression along with another medical illness tend to have more difficulty adapting to their medical condition, and more medical costs than those who do not have co-existing depression. Treating the depression can also help improve the outcome of treating the co-occurring illness.
There are several forms of depressive disorders. Major depressive disorder, or major depression, is characterized by a combination of symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Major depression is disabling and prevents a person from functioning normally. Some people may experience only a single episode within their lifetime, but more often a person may have multiple episodes.
Currently available pharmacological treatments for major depression are severely limited in their efficacy (Rush A J et al. Am J Psychiatry 2006; 163, 1905-1917). No more than a third of patients achieve remission on standard treatment and at least a third remains ill after a year or more of serial treatments.
The hormone L-3,3′,5,5′,-tetraiodothyronine (L-thyroxine or T4) is a product of the thyroid gland. Although thyroxine (tetraiodothyronine; T4) is the principal secretory product of the vertebrate thyroid, it's essential metabolic and developmental effects are primarily mediated by 3,3′,5-triiodothyronine (T3), which is produced from the prohormone by 5′-deiodination.
T4 is converted by one of three selenium-containing enzymes (deiodinases) into either the active hormone L-3,3′,5,-triiodothyronine (T3), the inactive T3 competitive product L-3,3′,5′-triiodothyronine referred to as reverse T3 (rT3) or, indirectly (by first being converted to T3) to the deactivated L-3,3′-diiodothyronine (3,3′-T2). Type I iodothyronine deiodinase (DIO1), a thiol-requiring propylthiouracil-sensitive oxidoreductase, is found mainly in liver and kidney and catalyzes conversion of T3 and rT3 by deiodination of the phenolic ring 5′ position iodine to form T3 or deiodination of the tyrosyl ring 5 position iodine to form rT3. Type II deiodinase (DIO2) is responsible for intracellular deiodination and its activity is limited to phenolic ring 5′ position deiodination to form T3 from T4. While the activity of DIO2 is similar to that of DIO1, DIO2 is primarily found in the thyroid, pituitary gland, brain, brown fat and testis. Type III deiodinase (DIO3) activity is limited to inner ring deiodination of T4 and T3 to the inactive rT3 and T2 products, respectively. DIO3 is primarily found in the brain, and can further be found in fetal tissues, placenta, skin and adipose tissue. DIO3 is not found in the heart or in bones. These reactions are illustrated in FIG. 1.
T3 is metabolically active and stimulates production of cellular energy, and generally is an activator of tissues and organs. T3 acts by diffusing into cells, where it interacts with a cellular protein which transports the T3 to the cellular nucleus. T3 then acts by stimulating gene transcription to produce messenger ribonucleic acids (mRNA) of certain genes. Translation of the T3-induced mRNA produces cellular proteins that promote cellular activation. In contrast, rT3 has opposing effects, at least partially by inhibiting the action of T3, by way of competitively inhibiting T3 nuclear receptors in cells.
The thyroid hormone, triiodothyronine (T3), is widely used to augment antidepressant action in depressed patients who have not responded to treatment with conventional antidepressants. While T3 is rarely used clinically as a monotherapy, the inventors of the present invention and co-workers have shown that chronic administration of the hormone has a dose dependent, antidepressant-like effect using screening tests including the forced swim test (FST), tail suspension test (TST) and novelty suppressed feeding test (NSFT) in mice (Lifschytz T et al. J. Pharmacol. Exp. Ther. 2011; 337, 494-502). Using in vivo microdialysis it has been also shown that chronic administration of T3 enhances serotonergic neurotransmission in rat frontal cortex and hypothalamus by functional desensitization of presynaptic 5-HT1A and 5-HT1B receptors which inhibit serotonin release (Lifschytz T et al. Curr. Drug Targets 2006; 7, 203-210). Moreover, when administered concurrently with fluoxetine (an anti-depressant also known by the tradename Prozac), T3 enhances neurogenesis in the rat hippocampus over and above the effect of fluoxetine alone (Eitan, R et al. Int J. Neuropsychopharmacol. 2010; 13, 553-561).
Although it has been suggested that administration of T3 can overcome depression symptoms it is not feasible to use T3 or synthetic analogs thereof as a first line treatment for depression because the hormone has significant effects on heart rate and bone density that limit long term use. Moreover, it has been recently shown that in mice the antidepressant effects of T3 are mediated by the same thyroid receptor subtypes responsible for T3 effects on heart rate and bone density (Lifschytz et al. 2011, ibid).
High expression of DIO3 with a crucial role in sustaining cell proliferation has been documented at sites of local inflammation, in the infarcted heart, during liver regeneration and in peripheral nerves after injury. DIO3 has also been shown to be re-expressed in various neoplastic tissues while remaining silent in the normal counterpart tissues. Elevated DIO3 mRNA and activity levels were shown in a variety of cancer cell lines including endometrium, neuroblastoma, colon, liver, basal cell carcinomas and breast cancer (Dentice M et al., Expert Opin Ther Targets, 2013; 17(11), 1369-79; Luongo C et al., Endocrinology 2014; 155(6), 2077-88) and in a number of human brain tumors (Nauman P et al., Folia Neuropathol 2004; 42(2), 67-73.). DIO3 expression has been found to be under the control of several signaling molecules and pathways that are major driving forces of cellular division, including HIF-1α, TGF and the Wnt-β-catenin pathway (Dentice M et al., J Endocrinol, 2011; 209(3), 273-82). It is thus proposed that DIO3 is under the control of an intricate circuit of signaling pathways that play a central role in the oncogenic process.
Elevating T3 concentration or the ratio of active T3 to non-active rT3 for treating various disorders has been suggested.
For example, PCT Patent Application Publication No. WO 03/099105 discloses methods for diagnosis and treatment of several disorders characterized by elevated serum ratio of rT3 to T3 defined as human dormancy syndrome. The treatment of human dormancy syndrome is directed toward increasing functional T3 levels or decreasing the inactive rT3 levels, or both, using pharmaceutical and/or behavioral methods, particularly via the modulation of type I deiodinase activity. Exemplified therein is the effect of T3 administration of several human dormancy syndrome disorders, depression being listed among the many other of the manifestations of this syndrome.
PCT Patent Application Publication No. WO 2006/028835 discloses the use of thyroid hormone conversion inhibitors to treat hyperproliferative skin disorders, preferably their use in topical admixtures. Particularly, the invention discloses the use of deiodinase inhibitors such as an iodinated contrast agent, e.g., iopanoic acid (IOP) and/or its analogs.
PCT Patent Application Publication No. WO 2008/140713 discloses methods for regulating the levels of type 3 iodothyronine deiodinase (DIO3) and or thyroid hormone in cancerous and pre-cancerous cells and related compositions and kits. siRNA and antisense oligonucleotides are suggested as DIO3 inhibitors.
PCT Patent Application Publication No. WO 2009/015366 discloses methods of treating conditions associated with hyperproliferation of cells, such as hirsutism, hypertrichosis, scar formation, ocular hyperproliferative disease, and pulmonary hyperproliferative disease, comprising administering thyroid hormone conversion inhibitor. In particular embodiments, the thyroid hormone conversion inhibitor is selected from the group consisting of iopanoic acid (IOP), ipodate, and propranolol.
Stoedter et al., published after the priority of the present invention, describe the effect of several selenocompounds containing a methyl- or benzyl-imidoselenocarbamate backbone on DIO expression in cancerous cells in vitro. A deferential effect was observed with the compounds examined, highlighting that these selenocompounds may constitute interesting pharmacological compounds for modifying DIO expression, potentially affecting the balance between cell differentiation and proliferation (Stoedter et al., Metallomics 2015; 7(2), 347-54).
U.S. Pat. No. 8,304,401 discloses methods for decreasing fat mass, increasing energy expenditure, increasing resistance to obesity, and lowering blood glucose levels in a subject with an agent that inhibits the expression or activity of type III deiodinase (DIO3). The inhibiting agent is an antisense, siRNA, siRNA-like, or ribozyme molecule and the agents of the invention are useful in treating diabetes and obesity.
An inventor of the present invention and co-workers have extensively studied the deiodination of thyroxine and related compounds, and have recently reported the first examples of synthetic compounds that functionally mimic DIO3 activity (FIG. 2) (Manna and Mugesh, Angew. Chem. Int. Ed. 2010; 49, 9246-9249; Manna and Mugesh, J. Am. Chem. Soc., 2011, 133, 9980-9983; Manna and Mugesh, J. Am. Chem. Soc. 2012; 134, 4269-4279).
To date, no effective specific inhibitors for Type III deiodinase (DIO3) are used as therapeutic compounds. DIO3 specific inhibitors could be efficient in treating diseases in which attenuating the expression and/or activity of this enzyme is desired, including depression in the context of major depressive disorder and bipolar disorder and depression associated with other diseases or conditions, and cancer.
There is an ongoing need for and it would be highly advantageous to have drugs which would inhibit cancerous states. Further, there is a critical and ongoing need for drugs for treating neuropsychiatric disorders and depression associated conditions that are specific and have minimal deleterious side effects.